Despite tremendous strides in understanding the molecular basis of cancer (1),.sup.1 treatment of human cancer is still limited by the toxicity of chemotherapeutic agents and the development of intrinsic or acquired resistance to these drugs. Cis-diamminedichloroplatinum (II) (cisplatin) is one of the most widely-used anticancer agents, active in the treatment of ovarian, testicular, head-and-neck, non-small cell lung and brain tumors, among others (2). However, the rapid development of resistance to cisplatin represents an important challenge to clinicians and laboratory investigators alike. Therefore, understanding the biochemical and molecular basis of cisplatin resistance may potentially result in the development of rational approaches to circumvent this problem. At the core of understanding cisplatin resistance lies the realization of both the similarities and differences between the mechanisms of cisplatin action and resistance and that of other chemotherapeutic agents. Cisplatin-resistant cells display a unique cross-resistance pattern to multiple agents, including anti-metabolites such as 5'-fluorouracil and methotrexate, DNA polymerase inhibitors such as azidothymidine (AZT), and topoisomerase inhibitors such as camptothecin and etoposide. This "atypical" multidrug resistance is both phenotypically and molecularly distinct from the "classical" multidrug resistance which may involve overexpression of the MDR-1 gene (3). FNT .sup.1 The bibliography precedes the claims.
A cursory review of the literature in cisplatin resistance quickly points to a potentially confusing array of mechanisms purported to be involved in this process, most of them seemingly disparate and unrelated. Recent advances in the workings of signal transduction in normal and cancer cells have led to a more cohesive picture of cellular pathways involved in the response to extracellular agents (e.g., growth factors, tumor promoters, viruses, and chemotherapeutic agents). This in turn has merged seemingly independent biochemical processes activated in response to various stimuli. An important molecular mechanism in cisplatin resistance concerns the c-fos proto-oncogene. The Fos protein dimerizes with the c-jun gene product to drive many important cell processes by transcriptional activation of AP-1-responsive genes (4). Numerous AP-1-responsive genes have been identified which participate in DNA synthesis and repair processes and which have been implicated in cisplatin resistance (5). These include metallothionein, DNA polymerase .beta., thymidylate synthase, topoisomerase II, and glutathione-S-transferase. Furthermore, the Fos/Jun heterodimers are thought to mediate the effects of H-ras activation following growth factor activation (6). And protein kinase C is a known participant in cellular signalling pathways leading to the activation of c-fos gene expression (4).